The objective of this proposal is to reveal molecular mechanisms by which stearoyl-CoA desaturase (SCD) expression partitions lipids between storage and oxidation. Understanding the basis of lipid homeostasis is fundamental to developing new strategies to combat obesity, diabetes and other diseases of abnormal lipid metabolism. SCD is a central enzyme catalyzing the synthesis of monounsaturated fatty acids, mainly oleate (C18:1), the major monounsaturated fatty acid of triglycerides, cholesterol esters, wax esters and phospholipids. Studies in the previous grant application demonstrated that mice with a targeted disruption of SCD1 isoform (SCD1-/-) have reduced lipogenic gene expression, increased fatty acid oxidation and enhanced insulin sensitivity. The SCD1-/- mice are leaner than control mice, resistant to both diet- and leptin deficiency-induced obesity and have reduced liver steatosis. The mechanisms by which SCD1 deficiency elicits the aforementioned phenotypes are still poorly understood. We have recently observed that despite an increase in plasma insulin upon feeding SCD1-/- mice with a high carbohydrate fat-free diet, the gene expression of peroxisome proliferator-activated receptor y co-activator (PGC-1a) including the fatty acid B-oxidation and gluconeogenic genes is increased in the fed state. Furthermore, the expression of the mature sterol regulatory element binding protein-1 (SREBP-1) is not increased and that of the SREBP-1c target genes is not induced. Interestingly, the gene expression and protein levels of insig-2a, a protein that blocks maturation of SREBPs by retaining them in the ER and is normally repressed by insulin is increased. Transgenic over expression of human SCD in mouse liver increases the expression of the mature SREBP-1 protein and that of lipogenic genes. We hypothesize that the cellular 18:1/18:0 ratio regulates hepatic lipid metabolism in the postprandial state by modulating the expression of PGC-1a and insig-2a proteins. We will design experiments to address this hypothesis using in vivo and in vitro approaches. The two specific aims of this proposal are: 1. To test whether hepatic SCD1 deficiency increases mitochondrial fatty acid B-oxidation in the postprandial state by regulating the expression of PGC-1a. 2. To test whether hepatic SCD1 deficiency blocks SREBP-1 processing and down regulates lipogenesis in the postprandial state by increasing insig-2a expression. Fat storage after a meal is one of the major causes of diet induced-obesity and type 2 diabetes. We have discovered a mechanism that partitions fat away from storage towards its burning in the fed state. Our research will contribute to the treatment of human obesity, diabetes and other metabolic diseases.